This proposal describes a five-year career development program whose goal is to prepare Ramy Arnaout for a role as a fully independent investigator in population immunology. This program will build on Dr. Arnaout's background in immunology, mathematics, and genomics and as a clinical pathologist by providing expertise in epidemiology. The principal guidance will be provided by a team of three mentors: Drs. Kenneth Mukamal, Associate Professor of Medicine at the Beth Israel Deaconess Medical Center (BIDMC; Dr. Arnaout's home institution), an expert epidemiologist; Bruce Psaty, Professor of Epidemiology at the University of Washington and an expert in genome-wide association; and Russell Tracy, Professor of Pathology at the University of Vermont, an expert in longitudinal cohort studies of immunity. They will be joined by experts in immunology (Hidde Ploegh, Professor Immunology at the Whitehead Institute) and genomics (Chad Nusbaum, co-director of the Genome Sequencing and Analysis program at the Broad Institute) as consultants. The training plan includes structured mentorship by this team, formal coursework in epidemiology at the Harvard School of Public Health, and a research program that will provide thorough training in epidemiology. In his preliminary studies, Dr. Arnaout has developed a pipeline for the high-throughput sequencing and characterization of B-cell repertoires, with a focus on V(D)J-recombined antibody heavy-chain genes. He has demonstrated this pipeline by sequencing repertoires of both humans and mice, a first-author publication. He then developed a mathematical approach for investigating repertoire diversity, and demonstrated its utility both by characterizing the repertoire diversity of murine peritoneal B-1a cells, which have unusual diversity characteristics, and via the surprising discovery of non-antigen-based selection in developing B-cell subsets in mice. In the current proposal, Dr. Arnaout will build on this work by applying his pipeline to a large human population-1,000 patients drawn from the widely used, data-rich NIH-funded Multi-Ethnic Study of Atherosclerosis (MESA)-to study the demographics, causes, and consequences of B-cell repertoire diversity. He will use samples and data from MESA, to which he has been granted access, to test (i) the cross-sectional association of B-cell diversity measures with age and with titers of various infectious agents; (ii) the longitudinal association of B-cell diversity measures with total mortality; and (iii) the genetic association between B-cell diversity measures and germline variation in VH, D, and JH gene segments and in the genes that encode the V(D)J recombination machinery. He will thereby discover the fundamental features of how B-cell repertoires vary in the population, with implications for infection and vaccination. This work will provide a foundation for future studies on the role of B-cell repertoires in population health as Dr. Arnaout achieves full independence in epidemiology.